Snake-venom Drug Battles Breast Cancer

NEW YORK, Aug 26 (Reuters) -- A protein found in snake venom may help prevent breast cancer from spreading to other body sites, researchers report.

The protein, called contortrostatin, "may represent a highly effective mechanism of maintaining breast cancer cells in a long-term dormant state and controlling cancer progression," say Drs. Francis Markland and Qing Zhou of the University of Southern California School of Medicine in Los Angeles, California. The findings were presented Wednesday at the annual meeting of the American Chemical Society in San Francisco.

Breast cancer is a leading cause of cancer death, claiming the lives of over 44,000 American women each year. However, the overall likelihood of patient survival remains high if the disease is detected before it has had a chance to spread to other body sites.

Unfortunately, research reveals that in about 60% of cases cancer has already spread beyond the breast at time of diagnosis.

The California researchers have been searching for compounds that might inhibit this spread. They focused on contortrostatin, a protein derived from southern copperhead snake venom, because it "possesses potent antitumor activity."

In studies of the protein in mice, the investigators found that breast cancer tumors were 60% to 70% smaller in contortrostatin-treated mice than in untreated mice.

"Even more exciting, the contortrostatin-treated group showed more than 90% inhibition of tumor spread to other sites in the body, as compared to the placebo group," according to a statement issued by the researchers.

Markland and Zhou believe the compound works by preventing tumor cells from sticking to healthy cells, thus preventing invasion of healthy tissue, and by preventing the growth of new blood vessels that tumors need to survive. This means that while contortrostatin may not reduce the size of existing tumors, it could hold them in check indefinitely. Therapies involving contortrostatin or similar drugs would thus need to be administered on a recurring basis, the authors say.

They believe that use of the compound could "also benefit cancer patients with other malignancies including prostate, bladder, melanoma, brain, and Kaposi's sarcoma."

Markland says trials involving breast cancer patients may start in "the not too distant future."

JNCI Journal of the National Cancer Institute 2001 93(4):261-262; doi:10.1093/jnci/93.4.261
© 2001 by Oxford University Press

Journal of the National Cancer Institute, Vol. 93, No. 4, 261-262, February 21, 2001
© 2001 Oxford University Press

Snake Venom Protein Paralyzes Cancer Cells

A component of snake venom has demonstrated its ability to inhibit cancer cell migration in two different cancer models. The protein, called contortrostatin, seems to block cell migration in a novel way.

Francis S. Markland, Ph.D., professor of biochemistry and molecular biology at the University of Southern California Keck School of Medicine, Los Angeles, was examining venom from the southern copperhead Agkistrodon contortrix contortrix for its clot-busting properties when he learned that a group in Taiwan had found disintegrins?integrin antagonists?in the venom of another snake.

 
Venom is obtained from snakes by "milking," as seen above with this copperhead.

"I thought it would be interesting to see if a similar protein was present in southern copperhead venom," recalled Markland in an interview. "But our initial studies showed no activity. The problem was that we were looking at its ability to inhibit platelet aggregation, and in the crude venom there are also platelet aggregating agents." After purifying the venom, Markland and his colleagues found a minor component of the venom that worked as a disintegrin, and this is the protein they named contortrostatin.

The integrins are a family of transmembrane receptor proteins that bind to components of the extracellular matrix. One of their functions is to grip the extracellular matrix, providing traction and allowing cells to migrate from one place to another. Researchers in a number of laboratories are focusing on one integrin in particular, called v3. This integrin is present on the surface of cancer cells and is thought to be critical in metastasis.

Contortrostatin appears to block cell migration both by binding to a cell-surface protein in the integrin family, preventing it from gripping the extracellular matrix, and by scrambling signals to the cytoskeleton.

"We knew on the basis of contortrostatin's ability to inhibit platelet aggregation that it was interacting with integrins, and we also knew that there are integrins on the surface of cancer cells," noted Markland. "Therefore we reasoned that it might be fruitful to look at its anticancer activity."

The group found that contortrostatin had very effective inhibitory properties on adhesion to several extracellular matrix proteins such as fibronectin and vitronectin. They also found that it was effective in inhibiting tumor cell invasion. Using human breast cancer cells and human ovarian cancer cells in immunodeficient mice given daily intratumor injections of contortrostatin, they discovered that it inhibited tumor dissemination and angiogenesis.

Moreover, the side effects were relatively minimal, said Markland. "There's some oozing at the side of the injections in the breast cancer model. And in the ovarian cancer model we've seen some petechiae [hemorrhagic spots], which is an anti-platelet effect. Aside from its effect on platelets, there have been minimal or no side effects, and certainly there has been no evidence of internal hemorrhaging."

Recently Matthew R. Ritter, a graduate student in Markland's lab, attempted to tease out contortrostatin's exact mechanism of action. What he found was a surprise, said Markland. The researchers expected contortrostatin to work the same way other disintegrins did, namely by interfering with v3's binding to extracellular matrix proteins. But contortrostatin apparently does more.

Integrins can bind to extracellular proteins only when they cluster in groups known as focal adhesions. Normally integrins are spread diffusely over the cell membrane, but when one molecule binds to its ligand it sends an intracellular signal that leads to the formation of a focal adhesion. In a poster session at the 40th Annual Meeting of the American Society for Cell Biology, Ritter and Markland (along with colleague Qing Zhou) reported that by crosslinking v3 integrins, contortrostatin caused intracellular signals that are both spatially and temporally inappropriate. These faulty signals disrupt both the focal adhesions and the actin cytoskeleton.

David A. Cheresh, Ph.D., a professor in the departments of immunology and vascular biology at the Scripps Research Institute, La Jolla, Calif., who works on integrins in angiogenesis and neoplasia, is intrigued by Markland's work, but in an interview he expressed some skepticism. In particular Cheresh noted that Markland maintains that contortrostatin acts as both an antagonist, since it blocks v3 binding to matrix proteins, and as an agonist, causing v3 to send a faulty signal.

"It's a very interesting molecule," said Cheresh. "It's a very exciting observation. I'm not sure, however, what the mechanism is, and I'm not sure how much of the biological activity they see in vitro is due to the agonistic effects or the antagonistic effects. It's a little hard to sort that out. I'm not sure you couldn't get a similar effect with just a decent antagonist. [Are] the signaling properties really critical to its biological activity?"

Cheresh said that there are two monoclonal antibodies to v3 integrin currently in phase II clinical trials. Vitaxin is being developed by MedImmune Inc., Gaithersburg, Md., and Cilengitide is being developed by Merck KgaA, Darmstadt, Germany. Markland said that although several pharmaceutical companies have expressed interest in contortrostatin, he has not yet developed a partnership with any of them to begin the clinical development.

And Cheresh cautioned that it may be a long road from the laboratory to the clinic. "Certainly in culture it's an interesting molecule. The question is, can one develop this toward cancer? One has to be concerned with the pharmacodynamic properties, and of course those are major stumbling blocks going from an interesting cell-biological observation, as these folks have made, to a potential drug candidate."

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